Immune-mediated diseases such as type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosis are reaching epidemic proportions in the US. T1D affects an estimated 3 million Americans, with more than 30,000 new patients diagnosed annually, resulting in roughly $15B in health care costs in the US each year. T1D is an autoimmune disease characterized by effector T-cell mediated destruction of insulin-producing ?-cells, which renders the patient unable to produce insulin and forces the patient to constantly monitor their glucose levels and manually administer insulin for the remainder of their life. Ultimately, glucose metabolism is interrupted, resulting in the development of life-threatening complications such as heart disease and renal failure. Clearly, the cost associated with treatment and care of T1D in the US is significant, both to society and the individual, and a novel therapy is desperately needed to thwart this aberrant autoimmune activity. This is a need that Onevax, LLC is committed to fulfilling. The biomedical research community has sought better ways to induce specific immune tolerance for nearly 50 years. Clinical intervention trials using immunomodulatory agents (e.g., anti-CD3) have failed to meet clinical endpoints, despite positive results in phase I/II trials. Moreover, traditional vaccine strategies providing auto-antigen or peptides alone failed to adequately block ongoing beta cell immunity. Thus, a new treatment strategy that is both potent and durable is required to effectively halt the ongoing attack in T1D. Regulatory T-cells (Tregs) provide an ideal target for immunomodulation as they are the cell type responsible for the maintenance of homeostasis in the immune system and create and maintain an anti-inflammatory milieu that fosters the establishment of immunological tolerance. Onevax has developed a tolerogenic vaccine approach using FDA-approved and GMP-compatible components in which Tregs will sense and respond dynamically, allowing for the execution of cellular programs far more precise in function than single target drugs commonly used today. The objective of this Phase I proposal is to establish the feasibility of using our novel, biomaterial-based, particle vaccine system for in viv delivery of the Treg growth factor IL-2 and insulin antigen to Tregs. Specifically, we will determine the ideal dosing and means of delivering IL-2 and immuno-modulatory factors in vivo allowing for efficacy studies of the vaccine system in animal models of diabetes. The results from these studies will allow us to proceed to Phase II of the SBIR, in which studies will be conducted to satisfy the FDA requirements for the production of a clinical-grade drug suitable for Human Phase I/II clinical trials as a novel therapy for T1D. Our long-term goal is to develop an easily injectable, modular particle-based vaccine capable of prevention and reversal of a wide variety of auto-immune diseases, greatly enhancing the potential for widespread use. Our preliminary data strongly suggests that this biomaterial-based, particle vaccine system holds promise for correcting autoimmune responses in T1D. Additionally, our strategic collaborations with the Biomedical Engineering Department and the Diabetes Center of Excellence at the University of Florida bolster our ability to complete the desired goals.